MS is a chronic inflammatory disease of the central nervous system characterized by prominent lymphocyte and macrophage infiltration into the white matter and by demyelination. This pathology is associated with neurological dysfunctions such as paralysis, sensory deficit and visual problems. The cause of the disease is unknown, but both environmental and genetic factors are important. Previous studies demonstrated that the HLA-DR2 (DRB1*1501) haplotype, an allele of a multi-gene family encoding antigen receptors known as MHC class II proteins, is present at increased frequency in northern European patients with MS (Spielman R. S., Nathenson N., Epidemiol. Rev. 4:45 (1982); Hillert J. et al., J. Neuroimmunol. 50:95 (1994); Oksenberg J. R. et al., JAMA 270:2362 (1993)).
Peptides that bind to MHC class II proteins have specific types of amino acid side chains at locations in the peptide sequence that are known as anchor positions. A variety of side chains at non-anchor positions are permitted, some of which are presented to T cells in a further step of an immune response (Rudensky A. Y. et al., Nature (London) 353:622 (1991); Hammer J. et al., J. Exp. Med. 176:1007 (1992); Hammer J. et al., Cell 74:197 (1993); Chicz R. M. et al., Nature (London) 358:764 (1992); Chicz R. M. et al., J. Exp. Med. 178: 27 (1993); Malcherec G. et al., Int. Immunol. 5:1229 (1993); Falk K. et al., Immunogenetics 39:230 (1994)). Approximately 350,000 people in the U.S. and 2.5 million people worldwide suffer from MS, which typically affects females who reside in Northern latitudes, from about age 20. Strategies for inducing immunological tolerance include blocking antigen presentation, supplying altered peptide ligands, developing tolerance by i.v. and oral administration, and blocking costimulatory molecules (Sakai K. et al., Proc. Natl. Acad. Sci. U.S.A. 86:9470 (1989); Hurtenbach U. et al., J. Exp. Med. 177:1499 (1993); Fairchild P. J. et al., Immunology 81:487 (1994); Brocke S. et al., Nature 379:343 (1996)).
However, there is no cure for MS, a disease which is ultimately fatal. There is a need for improved agents to treat MS and other demyelinating conditions.